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Digoxin and diuretics have been used for centuries to treat the symptoms of heart failure. Yet, it was the addition of angiotensin-converting enzyme (ACE) inhibitors that revolutionized the management of chronic heart failure by demonstrating an astonishing 40% reduction in 6-month mortality when compared to placebo in the original CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) (1). The evolution of evidence-based therapies makes it difficult to study new treatments without established background therapy. Thus, beta-blockers were studied in patients already treated with ACE inhibitors; other drugs such as angiotensin receptor antagonists and the combination of hydralazine and isosorbide dinitrate were studied in patients already treated with ACE inhibitors and beta-blockers. As a result of this evolution of evidence-based therapies, heart failure patients are now treated with a cocktail of medications often including ACE inhibitors, beta-blockers, digoxin, diuretics, aspirin, statins, and in some cases hydralazine and isosorbide dinitrate. These medications, in addition to medications used to treat concomitant conditions such as coronary artery disease, diabetes, and kidney disease, add to the expense of therapy and increase the likelihood for drug interactions, drug-related adverse effects (AEs), and noncompliance.

Mineralocorticoid receptor antagonists (MRAs), added to standard heart failure medications, reduce morbidity and mortality in patients with reduced ejection fraction and New York Heart Association (NYHA) functional class II to IV heart failure (RALES [Randomized Aldactone Evaluation Study] and EMPHASIS-HF [Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure]) (2,3) and in patients with acute heart failure following myocardial infarction (EPHUSUS [Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study]) (4). Despite the results of these important clinical trials, the use of MRAs in the treatment of heart failure with reduced ejection fraction (HFrEF) has not been widely adopted. The relevance of the RALES trial has been questioned because this study was done prior to the widespread use of beta-blockers and included only patients with advanced heart failure. Furthermore, clinicians became concerned about the safe use of MRAs in the general patient population when reports of excess hospitalizations for hyperkalemia and deaths were temporally linked to increased prescriptions of spironolactone in Ontario, Canada (5) following publication of the RALES trial. These concerns, along with patients' and providers' reluctance to “pile on another medication” have impeded the rapid addition of MRAs to the standard drug regimen for HFrEF.

In this issue of the Journal, Eschalier et al. (6) present a compelling subgroup analysis of the EMPHASIS-HF trial examining the use of the MRA epleronone in patients with HFrEF and NYHA functional class II heart failure symptoms. We now must face yet another challenge posed by the incremental nature of evidence-based therapies: Is it time to encourage all symptomatic heart failure patients to add MRAs to their list of medications? In the overall EMPHASIS-HF trial, epleronone reduced the combined endpoint of hospitalization for heart failure or cardiovascular mortality (the primary endpoint) by 37% (3). In the current substudy, the effect of epleronone on safety and outcomes were examined in patients commonly felt to be at highest risk for drug-related complications including subjects older than 75 years, with glomerular filtration rate <60 ml/min/1.73 m2, diabetes, and systolic blood pressure >123 mm Hg (the median systolic blood pressure in the EMPHASIS-HF trial). Eplerenone reduced the primary endpoint in all of the prespecified high-risk subgroups with convincing statistical significance. There was a significant increase in the incidence of hyperkalemia (K >5.5 mmol/l) in all high-risk subgroups but no increase in the incidence of severe hyperkalemia (>6.0 mmol/l), hospitalization for hyperkalemia, hyperkalemia leading to drug discontinuation, or hospitalization for worsening renal function. The authors conclude that there is compelling data for the use of eplerenone in carefully selected high-risk patients with NYHA functional class II HFrEF.

What should the clinician do now? This substudy of EMPHASIS-HF gives us new and compelling data to consider. The authors have shown that eplerenone is effective at reducing hospitalization for heart failure and cardiovascular mortality not only in aggregate among study participants, but also in patients representing high-risk subgroups. More interesting, however, the safety data suggest that there is not an increase in serious AEs including severe hyperkalemia and worsening renal function. At face value, these data imply that the predominance of patients with mild heart failure should be treated with MRAs.

However, there are several very important caveats. First, patients at highest risk for drug-related adverse events were excluded from the EMPHASIS-HF trial. Exclusion criteria included uncontrolled hypertension, baseline serum potassium >5.0 mmol/l, estimated glomerular filtration rate <30 ml/min/1.73 m2 and any other clinically significant comorbidities including mental illness, alcohol or chemical dependency, pre-existing liver disease, or the use of cytochrome P450 CYP 3A4 inducers or inhibitors. Second, the trial had a reduced dosing protocol for patients with chronic kidney disease (specifically those with an estimated glomerular filtration rate between 30 and 49 ml/min/1.73 m2). Finally, the laboratory monitoring protocol was very structured involving serum potassium assessments after every dose adjustment, and every 4 months thereafter. Dose adjustments were required whenever the potassium was 5.5 to 5.9 mmol/l and drug was discontinued if the potassium was ≥6.0 mmol/l, only to be restarted if the potassium on repeat testing was <5.0 mmol/l.

Therefore, we conclude that MRA therapy is an important addition to standard background therapy for stable, very carefully selected NYHA functional class II heart failure patients with an ejection fraction of ≤30% (35% or less if the QRS duration is >130 ms), treated with an ACE inhibitor or an angiotensin receptor blocker and a beta-blocker, unless contraindicated, at the recommended or maximally tolerated doses. All such patients should be part of an ongoing provider–patient relationship in an ambulatory care setting with robust mechanisms in place to closely follow patients for drug-related AEs. Outpatient tracking systems to ensure proper monitoring and dose adjustment should be mandatory prior to initiating therapy; electronic health records equipped with decision support and automated provider notifications may facilitate the safe implementation of MRA therapy. Because real-life clinical practice is filled with both human- and systems-related variables, we recommend careful case selection and monitoring before initiating MRA therapy.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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